Genetic variation occurs in all retrovirus infections including avian, murine and human retroviruses such as HIV. Mice inoculated with certain retroviruses generate variant retroviruses with altered infectious properties. The variants, which utilize a different cell surface receptor for infection, result from recombination of the inoculated virus with endogenous retroviral gene sequences of the mouse. Such variants have been implicated in a variety of proliferative diseases in the mouse. One of the outcomes of variant generation is a mixed retroviral infection in which the host is infected with two or more types of viruses with differing infectious properties. Our recent studies have focussed on the interaction of murine retroviruses in mixed infections. Two modes of mixed retroviral infection have been examined. The first is a mixed infection generated by inoculation of a lymphocytic leukemia-inducing virus which readily recombines with host genes to generate host range variants. It is known that the generation of variants is necessary for this disease and it is established that the induction of leukemia is the result of the activation of host proto-oncogenes by integration of viruses in close proximity to such genes. However, since both the inoculated virus and the variants are capable of proto-oncogene activation, the requirement for host range variants is unclear. We have found that the interaction of the two virus types through pseudotyping and interference during the preleukemic phase of disease results in two distinct phases of rapid infection of the target cells. It is likely that this infectious process facilitates a highly efficient stepwise mechanism of leukemogenesis. We have also examined mixed retroviral infections generated by co-inoculation of retrovirus mixtures. We have found that co-inoculation of an erythroleukemia virus with a virus which induces a low incidence of neurological disease after a relatively long latency (3-6 months) in NFS/N mice, results in a fatal neurological disease starting 10 days after inoculation. This disease is the most rapidly fatal disease induced by any reported retrovirus with virtually all co-inoculated mice moribund or dead within two weeks after infection. We have recently established that the gene encoding the erythroleukemia viral envelope glycoprotein is responsible for this effect. Further studies are directed at quantification of viral pseudotyping in co-inoculated mice and the effect of co-inoculation on the infection and distribution of both virus types in the central nervous system.